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MK-5172

现货
Catalog No.
A3618
HCV NS3/4A蛋白酶抑制剂
组合的产品项目
规格价格库存 数量
10mM (in 1mL DMSO)
¥ 1,180.00
现货
5mg
¥ 900.00
现货
10mg
¥ 1,400.00
现货
50mg
¥ 4,500.00
现货
100mg
¥ 6,500.00
Ship with 10-15 days

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Background

MK-5172 is a selective inhibitor of Hepatitis C Virus NS3/4a Protease [1].
Hepatitis C (HCV) virus is a member of the Flaviviridae family of viruses in the Hepacivirus genus and encoded by a 9.6-kb positive strand RNA genome [2].
In biochemical assays, MK-5172 inhibited a series of major genotypes and common mutants in a HCV NS3/4A protease enzymatic assay. In a cell-based replicon system, MK-5172 inhibited HCV with EC50 values of 2 nM against genotype 1a, 0.5 nM against genotype 1b, 8 nM against genotype 2a and 13 nM against genotype 3. Also, MK-5172 is effective against HCV genotypes 1a, 2a, 1b, 2b and 3a [2].
Treatment three chronically HCV-infected chimpanzees with a dose of 1 mg/kg twice daily for 7 days, Two of the chimpanzees had wild-type (WT) gt1a or gt1b infections with high viral titers (~106 IU/ml). A third chimpanzee had a modest viral titer (~104 IU/ml) that was gt1a NS3 R155K virus. MK-5172 (1 mg/kg) reduced viral titer of the gt1a (WT) infection to ~100 IU/ml within 2 days and the gt1b infection to 20 IU/ml. The gt1a NS3 R155K-infected chimp experienced a rapid ~2-log reduction in viral titer [2].
References:
[1]. Harper S, McCauley JA, Rudd MT, et al. Discovery of MK-5172, a Macrocyclic Hepatitis C Virus NS3/4a Protease Inhibitor. ACS Med Chem Lett, 2012, 3(4): 332-336.
[2]. Summa V, Ludmerer SW, McCauley JA, et al. MK-5172, a selective inhibitor of hepatitis C virus NS3/4a protease with broad activity across genotypes and resistant variants. Antimicrob Agents Chemother, 2012, 56(8): 4161-4167.

文献引用

1. Ng TI, Tripathi R, et al. "In Vitro Antiviral Activity and Resistance Profile of the Next-Generation Hepatitis C Virus NS3/4A Protease Inhibitor Glecaprevir." Antimicrob Agents Chemother. 2017 Oct 30. pii: AAC.01620-17. PMID:29084747

Chemical Properties

Physical AppearanceA solid
StorageStore at -20°C
M.Wt766.9
Cas No.1350514-68-9
FormulaC38H50N6O9S
SynonymsMK 5172;MK5172,Grazoprevir,
Solubility≥38.35 mg/mL in DMSO, ≥24 mg/mL in EtOH with ultrasonic and warming, <2.27 mg/mL in H2O
SDFDownload SDF
Canonical SMILESCOC1=CC2=C(N=C(CCCCC[C@@H]3C[C@H]3OC(N[C@@H](C(C)(C)C)C(N4[C@H](C(N[C@@]5(C(NS(=O)(C6CC6)=O)=O)[C@H](C5)C=C)=O)C[C@@H]7C4)=O)=O)C(O7)=N2)C=C1
运输条件试用装:蓝冰运输。 其他可选规格:常温运输或根据您的要求用蓝冰运输。
一般建议为了使其更好的溶解,请用37℃加热试管并在超声波水浴中震动片刻。不同厂家不同批次产品溶解度各有差异,仅做参考。若实验所需浓度过大至产品溶解极限,请添加助溶剂助溶或自行调整浓度。

试验操作

激酶实验 [1]:

抑制试验

使用时间分辨荧光测定中测定含有MK-5172、vaniprevir或参考化合物丹那普瑞和TMC435的反应混合物中HCV NS3/4A蛋白酶活性的抑制。在10%胎牛血清(FBS)或40%正常人血清(NHS)存在下,在基因型1b(con1)稳定细胞系HB1(26)或gt2a细胞系(JFH)中进行基于细胞的HCV复制子测定。对于体外抗性选择,将100,000个HB1细胞接种到T162Z-顶烧瓶中,并在0. 5mg/ml G418和所需浓度的MK-5172存在下培养。将细胞培养约3周,定期更换培养基,直到发生足够的细胞死亡,以形成不同的菌落。扩增后,分离总RNA,用作模板产生NS3/4a cDNA,并使用常规分子生物学技术进行测序。

细胞实验 [1]:

细胞系

含有基因型/突变体组的稳定复制子细胞系

溶解方法

该化合物在DMSO中的溶解度大于38.4 mg/mL。若获取更高浓度的溶液,可在37℃下孵育10分钟,随后在超声波浴中摇匀。-20℃以下可储存数月。

反应条件

2-10 nM,3周

应用

MK-5172针对基因型1a、1b和2a具有亚纳摩尔至低纳摩尔EC50。MK-5172在临床中遇到的基因型1感染的基因多样性范围内有效,EC50s范围在0.3至5.9 nM之间。在基因型1b复制子细胞中,MK-5172预处理导致很少的细胞生长和复制子RNA水平的有限恢复。

动物实验 [1]:

动物模型

黑猩猩、狗、大鼠

给药剂量

口服,1 mg/kg,每天2次,持续7天

应用

MK-5172表现出低至中等的清除率,在大鼠和狗中的半衰期均适中。口服给药MK-5172(1 mg/kg)表现出12至13%的适度生物利用度,两种物种中均具有中等程度血浆暴露。在大鼠中,24小时的肝脏浓度为0.2 μM,狗中(1 mg/kg)为1.4 μM,产生比血清调节的复制子EC50高27至200倍的曝光倍数。在携带gt1a、gt1b或gt1a NS3 R155K感染的慢性HCV感染的黑猩猩中,MK-5172(1 mg/kg,每天2次)处理在体内表现出有效性。

注意事项

由于实验环境的不同,实际溶解度可能与理论值略有不同,请测试室内所有化合物的溶解度。

References:

[1]. Summa, V., Ludmerer, S. W., McCauley, J. A., Fandozzi, C., Burlein, C., Claudio, G., ... & Gates, A. T. (2012). MK-5172, a selective inhibitor of hepatitis C virus NS3/4a protease with broad activity across genotypes and resistant variants. Antimicrobial agents and chemotherapy, AAC-00324.

质量控制

化学结构

MK-5172

相关生物数据

MK-5172